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* Department of Trauma Surgery, Hannover Medical School, Hannover, Germany;
Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria;
Department of Medical Microbiology, Hannover Medical School, Hannover, Germany;
Department of Orthopedic Surgery, Division Orthopedic Traumatology, University of Pittsburgh, Pittsburgh, PA 15213; and
¶ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
The PI3K/Akt signaling pathway has been recently suggested to have controversial functions in models of acute and chronic inflammation. Our group and others have reported previously that the complement split product C5a alters neutrophil innate immunity and cell signaling during the onset of sepsis and is involved in PI3K activation. We report in this study that in vivo inhibition of the PI3K pathway resulted in increased mortality in septic mice accompanied by strongly elevated serum levels of TNF-
, IL-6, MCP-1, and IL-10 during sepsis as well as decreased oxidative burst activity in blood phagocytes. PI3K inhibition in vitro resulted in significant increases in TLR-4-mediated generation of various proinflammatory cytokines in neutrophils, whereas the opposite effect was observed in PBMC. Oxidative burst and phagocytosis activity was significantly attenuated in both neutrophils and monocytes when PI3K activation was blocked. In addition, PI3K inhibition resulted in strongly elevated TLR-4-mediated generation of IL-1
and IL-8 in neutrophils when these cells were costimulated with C5a. C5a-induced priming effects on neutrophil and monocyte oxidative burst activity as well as C5a-induced phagocytosis in neutrophils were strongly reduced when PI3K activation was blocked. Our data suggest that the PI3K/Akt signaling pathway controls various C5a-mediated effects on neutrophil and monocyte innate immunity and exerts an overall protective effect during experimental sepsis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Hochschulinterne Leistungsfoerderung-1 Grant (Hannover Medical School, Hannover, Germany) and by Deutsche Forschungsgemeinschaft Grant RI 1216/4-1 (German Research Council (Deutsche Forschungsgemeinschaft)).
2 C.D.W. and N.A.T. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Niels C. Riedemann, Department of Trauma Surgery, Medizinische Hochschule Hannover, Carl Neuberg Strasse 1, 30625 Hannover, Germany. E-mail address: nriedeman{at}yahoo.com
4 Abbreviations used in this paper: FKHR, forkhead-related transcription factor; CLP, cecum ligation and puncture; DPBS, Dulbecco’s PBS; GSK, glycogen synthase kinase; KC, keratinocyte-derived chemokine; MFI, mean fluorescence intensity.
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